Virus-specific CD8+ T-cell memory determined by clonal burst size

Abstract

Although some viruses, particularly the herpes viruses, may never be eliminated from the body, others like influenza A, regularly reinfect humans and boost waning crossreactive CD8+ T-cell immunity. Prolonged T-cell memory is found for viruses that are unlikely to be re-encountered and which do not persist in the host genome, indicating that CD8+ T-cell memory might be independent of continued (or sporadic) antigenic exposure. A feature of virus-specific CD8+ T-cell memory is that antigen-specific cytotoxic T-lymphocyte precursors (CTLp) are greatly increased and remain high throughout life. The idea that persistence of the inducing antigen is essential is based on experiments in which adoptively transferred CD8+ memory T cells could not be detected for more than a few weeks in naive recipient mice without secondary challenge. Here we show that restimulation of such chimaeric mice with an inducing Sendai virus antigen increases the clonal burst size more than 7-fold within 8 days, making memory CTLp easier to detect in the longer term. We find that Sendai-virus-specific CTLp are maintained for > 250 days in irradiated uninfected recipients, including reconstituted beta 2-microglobulin-/- mice. To determine whether a source of viral peptide can persist after primary infection, we gave Sendai-virus-specific Thy1.1+ memory spleen cells to naive mice that had been minimally depleted of Thy1.2+ T cells, or to comparable recipients that had recovered from infection with Sendai virus or influenza virus. Although antibody against Sendai virus was never found in the naive recipients, Sendai-virus-specific CD8+ memory T cells were maintained equally well in each case for > 100 days after cell transfer. We find no evidence for persisting depots of viral protein that might feed into the endogenous processing pathway and maintain virus-specific CD8+ T-cell memory.

Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment

“…The CFSE dilution analyses described here indicated that increases in cell survival were likely to contribute significantly to the magnitude of the initial clonal T cell burst, which has been reported previously to predict the extent to which protective immunity is established [1]. However, the means by which TLR agonists promote T cell survival remain unclear.…”

“…For example, the initial burst size of an anti-viral T cell response is correlated with long-term immunity [1], but unconstrained clonal expansion can lead to immunopathological effects [2]. Conversely, poor expansion or expansion in the absence of differentiation fails to establish immunity, and may even reinforce tolerance by generating cells with antigen-specific T regulatory function [3][4][5].…”

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

“…Similar findings have been obtained with replication competent WT HSV (data not shown). These data are in agreement with the notion that the amount of memory CTL is directly proportional to the clonal burst size of the corresponding primary response [14,15]. Together, our data indicate that CTL priming in DC-MHCI mice yields more effector and memory CTL as compared with C57BL/6 mice.…”

“…This expansion is followed by a contraction phase when 90-95% of effector cells die by apoptosis and the surviving Ag-specific CD8 1 T cells form the memory T-cell pool. The resulting memory CD8 1 T-cell numbers are typically proportional to the peak in primary T-cell expansion [14,15] and elevated memory CD8 1 T-cell numbers can correlate with increased protection from re-infection [16,17]. Consequently, strategies to improve vaccines try to manipulate signals to optimize primary expansion of naïve CD8 1 T cells in order to generate the highest possible number of memory T cells.…”

Cellular Immune Recognition and the Biological Role of Major Transplantation Antigens

“…T-cells are critical for controlling persisting noncytopathic viruses that hide in peripheral epithelial or mesenchymal cells and prevent them from re-emerging to trigger T-cell mediated immunopathological disease (Table 4). There is good evidence available now that these protective T-cells are also maintained by antigens [106,110,111], although this simple notion is very controversial at the present time [102,112,113]. Thus, low levels of ongoing T-cell responses reflect antigen-driven activated effector T-cells and not special memory T-cells.…”